Method for treating overactive bladders and a device for storage and administration of topical oxybutynin compositions

ABSTRACT

The invention relates to a method for treating overactive bladders and a device for storing and administering non-occluded oxybutynin topical compositions.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a method for treating over activebladders and a device for storing and administering topical oxybutynincompositions. More specifically, the present invention relates to adevice for storing and administering a non-occluded oxybutynincomposition such as gels, creams and lotions. The device may be sized tostore single or multiple doses of the topical oxybutynin compositionthat can be used to treat patients with over active bladders.

BACKGROUND OF THE INVENTION

Oxybutynin is an anticholinergic, antispasmodic agent that has beenknown since the mid 1960s and has been used for the treatment ofoveractive bladder and urinary incontinence. Oxybutynin has a chiralmolecular center and may be present as a racemic mixture or in purifiedisomeric forms. Oxybutynin, as well as the purified isomeric forms, canbe prepared as a free base or as a pharmaceutically acceptable salt formsuch as the chloride salt. Oxybutynin is metabolized todesethyloxybutynin which is believed to have pharmacological activitysimilar to oxybutynin.

Oxybutynin has been commercially available in the form of oral syrups,immediate release tablets, controlled release osmotic tablets andtransdermal patches. Examples of oral controlled release oxybutyninformulations are disclosed in U.S. Pat. Nos. 5,674,895; 5,912,268;6,262,115 and 6,919,092. The oral administration of oxybutynin is knownto cause a number of adverse side effects. The primary adverse sideeffect is dry mouth, however, adverse events such as abdominal pain, drynasal and sinus mucous membranes, constipation, diarrhea, nausea,somnolence, dizziness, impaired urination, increased post void residualvolume and urinary retention have been reported.

It has been discovered that the incidences of adverse events can bereduced by the transdermal administration of oxybutynin. Transdermaloxybutynin patches are described, for example, in U.S. Pat. Nos.5,164,190; 5,601,839; 6,743,441 and 7,081,249. Examples of non-occludedoxybutynin topical compositions are described, for example, in U.S. Pat.Nos. 7,029,694; 7,194,483 and 7,425,340. It has been reported that thetransdermal administration of oxybutynin results in a reducedoxybutynin:desethyloxybutynin ratio in the plasma compared to the oraladministration of oxybutynin. This reduced oxybutynin:desethyloxybutyninratio via transdermal administration results in less adverse events.

Although oxybutynin transdermal patches and non-occluded topicalcompositions are known in the art and provide the benefits of oxybutyninwithout the increased side effects of oral administration, thedevelopment of a suitable device, container and/or packaging system forstoring and administering non-occluded oxybutynin topical compositionshas been problematic. Specifically, the storage and administrationdevice needs to provide an accurate and consistent dose of oxybutynin toinsure the patient receives the necessary therapeutic amounts of thedrug. The device also needs to provide a stable and robust environmentfor the non-occluded oxybutynin topical composition. With respect tostability, the device must prevent the non-occluded oxybutynin topicalcomposition from degrading over time, reacting with the materialsforming the device and leaching or permeating through the device.

The stability of non-occluded oxybutynin topical compositions furtherpresents many unique issues because the non-occluded oxybutynin topicalcompositions often contain a high solvent content, i.e., water oralcohol. The high solvent content may promote reactions with thematerials forming the storage and administration device. The solvent mayalso evaporate, leach and/or permeate from the storage andadministration device over time thereby resulting in a decreased skinflux when the non-occluded oxybutynin topical composition is dispensedand applied to a patient's skin.

Further stability complications can occur when oxybutynin chloride isemployed. The large volume of solvent in the non-occluded oxybutynintopical composition will allow the oxybutynin chloride salt todisassociate, creating free chloride ions that may cause furtherunwanted reactions with materials forming the storage and administrationdevice.

A device for storing and administering non-occluded oxybutynin topicalcompositions must also be strong, durable and useable. Specifically, thedevice must protect the non-occluded oxybutynin topical composition fromaccidentally or prematurely being dispensed or expelled from the device.For example, the device may be inadvertently squeezed, crushed orcompressed during storage and transport to the patient. The device mustwithstand these inadvertent compressive forces without bursting butallow the patient to easily open and dispense the non-occludedoxybutynin composition.

Containers for cosmetic and pharmaceutical products such as alcoholpads, transdermal patches and perfumes are described in the art. Forexample, WO 90/05683 describes a heat sealed sachet that can be used tostore cosmetic and pharmaceutical materials wherein the layers of thesachet can be peeled apart to allow access to the stored materialwithout touching the stored material. This structure would not be usefulfor a non-occluded oxybutynin topical composition because the sealingbond strength is low and may causing unwanted bursting.

Another container is disclosed in WO 85/03275 which describes acontainer for an alcohol preparation device that employs a fluidretaining pad sandwiched between two fluid impermeable layers. Stillother flexible containers are taught in GB 515,876 as well as in U.S.Pat. Nos. 4,998,621; 5,268,209; 5,400,808; 6,326,069; and 6,905,016.These prior container systems employ support structures for storedmaterials.

None of these prior containers suggest their use with a non-occludedoxybutynin topical composition, and, more importantly, a way to overcomethe stability, strength and durability issues encountered when preparinga device for storing and administering a non-occluded oxybutynin topicalcomposition.

It is an object of the present invention to provide a device for storingand administering a non-occluded oxybutynin topical composition that canprovide an accurate and consistent dose of oxybutynin to a patient.

It is a further object of the present invention to provide a device forstoring a non-occluded oxybutynin topical composition that provides astable environment for the non-occluded oxybutynin topical compositionfor at least one year or longer.

It is another object of the present invention to provide a device forstoring and administering a non-occluded oxybutynin topical compositionthat is strong, durable and robust to avoid unwanted and accidentalruptures or bursts under pressure of at least 20 pounds, preferably atleast 25 pounds and most preferably at least 30 pounds of pressure ormore.

It is still a further object of the present invention to provide adevice for storing and administering a non-occluded oxybutynin topicalcomposition that is easy to manufacture and is free of any rigidstructural support mechanisms.

It is yet another object of the present invention to provide a devicefor storing and administering a non-occluded oxybutynin topicalcomposition that is easy to open and from which the non-occludedoxybutynin topical composition is easily dispensed.

It is still another object of the present invention to treat humanpatients suffering from overactive bladder by providing to a patient asingle or daily dose of a therapeutically effective amount of anon-occluded oxybutynin topical composition in a flexible storagedevice, removing or dispensing the single or daily dose of thenon-occluded oxybutynin composition from the flexible storage device andtopically applying the single or daily dose of the non-occludedoxybutynin composition to the patient's skin.

These and other objects of the present invention will become apparentfrom a review of the appended specification.

SUMMARY OF THE INVENTION

The present invention accomplishes the above objects and others bycreating a device or a flexible container such as a pouch or sachet thatis formed from a laminate material comprising, from inside out, a firstpolymer layer, an adhesive layer and a metal foil layer wherein theadhesive layer adheres the first polymer layer to the metal foil layer.The laminate may further comprise additional layers. The additionallayers may be polymeric, paper or adhesive layers and may be between thefirst polymer layer and the metal foil layer or on the outer surface(away from the oxybutynin composition) of the metal foil layer. Oneembodiment of the present invention will further comprise an outerprinting layer that will allow the device to be printed or embossed withdescriptive, decorative and/or instructional information.

The first polymer layer will be in direct contact with the non-occludedoxybutynin composition and should comprise a polymer or copolymer thatis substantially inert to the oxybutynin composition. Examples ofmaterials that may be used to form the first polymer layer include, butare not limited to, polyethylene and acrylic based polymers orcopolymers such as a methyl acrylate or acrylic acid.

The metal foil layer will provide a vapor barrier for the device andprevent the evaporation of the solvents from the non-occluded oxybutynincomposition stored in the device. The metal foil should also prevent thepermeation of materials from the external environment into thenon-occluded oxybutynin composition. An example of a useful metal foilis aluminum with a thickness of about 0.20 mils to about 0.5 mils.

The device may be prepared by bringing two sheets of the laminatetogether so the first polymer layers are in contact (opposing), forminga reservoir for the non-occluded oxybutynin composition, placing thenon-occluded oxybutynin composition into the reservoir and sealing thedevice. In one embodiment of the present invention, the steps of formingthe reservoir and sealing the device are accomplished by heat sealing.

The device may also be prepared by folding the laminate so the firstpolymer layer comes into opposing contact, sealing two of the open edgesof the folded structure thereby creating a reservoir for thenon-occluded oxybutynin composition, placing the non-occluded oxybutynincomposition into the reservoir and sealing the final (open or fill) edgeof the folded structure.

After the device is prepared, i.e. filled with a non-occluded oxybutynincomposition and sealed, it should provide a safe, durable and stableenvironment for the non-occluded oxybutynin composition for at least oneyear, preferably 18 months, most preferably 24 months or longer. Thefinal prepared device should also allow a patient in need of oxybutynintherapy to easily open the device and dispense an accurate andconsistent dose of the non-occluded oxybutynin composition for topicaladministration. The opening of the prepared device by the patient may befacilitated by notching or partially scoring a section of one of thesealed edges.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top planar view of one embodiment of the present invention.

FIG. 2 is cross sectional view of the embodiment of the present shown inFIG. 1 taken along line 2-2 of FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “device” and “container” are usedinterchangeably and are broadly defined to refer to any flexiblepackaging system such as a sachet or pouch that is designed to hold,store and transport an accurate and reproducible amount of anon-occluded oxybutynin topical composition. In one embodiment of thepresent invention, the device or container should contain an amount of anon-occluded topical oxybutynin composition that will provide a singledaily therapeutic dose or a multiple therapeutic dose of oxybutynin. Forexample, in one embodiment of the present invention the device orcontainer may contain 0.25 g to about 5 grams of a non-occluded topicaloxybutynin gel wherein about 3% to about 15% based upon the total weightof the gel is oxybutynin.

As used herein, the term “oxybutynin” refers to oxybutynin in its freebase form as well as pharmaceutically acceptable salts thereof. It alsoincludes racemic mixtures or purified isomeric forms of the free baseand pharmaceutically acceptable salts thereof.

The term “topical” means a composition suitable for direct applicationto a skin surface and from which a therapeutically effective amount ofthe oxybutynin is released for transdermal administration to a patientin need of oxybutynin therapy. Examples of topical compositions include,but are not limited to, gels, lotions and creams.

The term “non-occluded” as used herein refers to a composition appliedto the skin without the use of a supporting structure. In other words, anon-occluded topical composition is directly applied to the skin in afree form, which is sufficient to effect transdermal delivery ofoxybutynin without the use of a support structure such as a backingmember typically used for transdermal patches.

Referring to FIGS. 1 and 2, the device 1, in accordance with the presentinvention, comprises a laminate that is processed to form a reservoir 3for the non-occluded oxybutynin composition 5. The reservoir 3 may beprepared by joining or sealing two sheets of opposing laminate materialalong all its edges 4 or from a single sheet of the laminate that hasbeen folded into an opposing structure and sealed along its edges 4. Thedevice 1 may be in any design, shape or form, irregular or uniform.Uniform shapes such as squares, rectangles, circles and ovals arepreferred in order to facilitate the sealing and manufacturingprocesses. The dimensions of the device 1 will be designed so thereservoir 3 can easily accommodate the desired amount of thenon-occluded oxybutynin composition 5.

As shown in FIG. 1, the reservoir 3 may be formed with a narrowed orconical region to allow the dispensing of the non-occluded oxybutynincomposition 5 from the device is a uniform, narrow and consolidatedstream. The device 1 may also contain one or more notches 20 that willallow the user to open the device 1 and dispense the non-occludedoxybutynin composition 5 from the device 1 for application to apatient's skin. The notch 20 may be a horizontal or angular slit formedinto one or more of the edges of the device. The notch 20 may also beformed by removing a portion of the laminate along the sealed edges.

The sealing of the edges of the device 1 can be accomplished by heat,ultrasound, laser, or adhesive and the like. One embodiment of thepresent invention employs a self-sealing mechanism (i.e., able to form astable bond between two facing surfaces of the same material without theuse of an adhesive). An example of an acceptable self-sealing mechanismis heat sealing. The seal may be a destructive seal which means the sealshould form a bond whose strength equals or exceeds the bond strength ofthe bond joining the layers of the laminated.

The seal strength can be determined by use of a motorized test standwhich slowly squeezes the finished device between two platens. Aninadequate seal will be evident if the non-occluded oxybutynincomposition 5 is forced out of the sealed or finished device 1 at apressure lower than 20 pounds. An acceptable seal should with standpressure of at least 20 pounds, preferably at least 30 pounds and mostpreferably at least 50 pounds without bursting. One embodiment of thepresent invention is able to withstand 20 to 100 pounds of pressurewithout bursting, preferably 25 to 80 pounds of pressure withoutbursting and most preferably 30 to 75 pounds of pressure withoutbursting. These pressures simulate the effect of pressures experiencedduring routine handling in packaging and patient use.

The laminate used in preparing the present invention should comprise afirst polymer layer 14 that will contact the non-occluded oxybutynincomposition and a metal foil layer 10 bonded to the first polymer layer14. The first polymer layer 14 may be a thermoplastic polymer that doesnot substantially absorb, react with, or otherwise adversely affect theoxybutynin or other excipients or components used in the non-occludedoxybutynin composition 5. Examples of a thermoplastic material that canbe used for the first polymer layer 14 are nitrile rubber modifiedacrylonitrile-methyl acrylate copolymers. Such materials are disclosed,for example, in U.S. Pat. No. 3,426,102, and are commercially sold underthe trademark BAREX®. Another thermoplastic polymer that may be used asthe first polymer layer is a polyethylene polymer or copolymer. Examplesof suitable polyethylene polymers include, but are not limited to, lowdensity polyethylene (LDPE) and linear low density polyethylene (LLDPE).

The thickness of first polymer layer 14 may be about 0.5 mil to about2.5 mil, more preferably from about 0.75 mil to about 1.5 mil, and evenmore preferably from about 1.0 mil to about 1.5 mil. While thinner andthicker widths may be employed, the first polymer layer 14 should not beso thin so as to compromise its permeation and stabilizing properties,nor so thick so as to adversely affect its self-sealing and packagingproperties.

The first polymer layer 14 is adhered or attached to the metal foillayer 10, such as aluminum foil, by any technique known in the art.Attachment by means of heat fusion or an adhesive layer 12, arepreferred. Use of an adhesive layer 12 is preferred in order to achievegreater tear resistance properties which are desirable in creating childresistant/proof packaging.

Suitable adhesives that may be used to adhere or bind the first polymerlayer 14 to the metal foil layer 10 include, but are not limited to,urethanes and ethylene/acrylic acid copolymers. Other examples ofsuitable adhesive materials are described in U.S. Pat. Nos. 4,359,506and 5,268,209. The adhesive 12 should be selected so it creates adestructive bond between the metal foil layer 10 and the first polymerlayer 14. The adhesive may be applied to metal foil and dried to athickness that should preferably not exceed about 1 mil, and ispreferably in a range from about 0.3 mil to about 0.75 mil.

The metal foil layer 10 may be a thickness of about 0.20 mil to about0.50 mil, preferably about 0.25 mil to about 0.40 mil.

The laminate employed in the present invention may comprise additionallayers between the first polymer layer 14 and the metal foil layer 10and/or on outer or external surface of the metal foil layer 10. Theadditional layers may provide additional strength and stability to thedevice 1. One embodiment of the present invention includes an additionalexternal layer such as a paper or polymeric layer that will allowprinting or embossing of indicia onto the outer most surface of thedevice.

Examples of non-occluded oxybutynin composition 5 that may be used inthe present invention are described in U.S. Pat. No. 7,179,483, and inparticular examples 3-21, which are incorporated herein by reference.Additional examples of non-occluded oxybutynin compositions that may beused in the present invention are described in U.S. Pat. No. 7,425,340.

One embodiment of the present invention is designed for use with anon-occluded oxybutynin gel composition, preferably an oxybutyninchloride gel. The gel comprises oxybutynin or a pharmaceuticallyacceptable salt thereof, a solvent and a thickening agent.

The oxybutynin is present in the gel in an amount of about 2% to about20% based upon the total weight of the gel, preferably about 4% to about15% based upon the total weight of the gel and most preferably about 8%to about 12% based upon the total weight of the gel.

The solvent should comprise at least 50% of the total weight of the gel,preferably at least 60% or more of the total weight of the gel and mostpreferably at least 70% or more based upon the total weight of the gel.The solvent preferably is an organic solvent or a mixture of water andan organic solvent. The organic solvent should be safe when applied tothe human skin and have a relatively low boiling point, i.e., less than100° C., to allow the quick evaporation when the gel is applied to apatient's skin. Examples of organic solvents that are useful in creatinggels for use with the present invention include C₁ to C₆ hydrocarbons,preferably C₁ to C₆ alcohols such as methanol, ethanol, isopropylalcohol, benzyl alcohol, propanol and mixtures thereof. If awater:organic solvent mixture is employed as the solvent for theoxybutynin gel, the ratio of water to organic solvent should range fromabout 1:2 to about 1:20, preferably about 1:3 to about 1:12 and mostpreferably about 1:5 to about 1:10.

One embodiment of the present invention employs a non-occludedoxybutynin gel composition that comprises at least 50% of the totalweight of the gel of a volatile organic solvent, preferably at least 60%or more of the total weight of the gel of a volatile organic solvent andmost preferably at least 65% or more based upon the total weight of thegel of a volatile organic solvent.

The thickening agent may be a compound of high molecular weight whichacts to produce a semisolid, viscous solution or suspension-typeformulation. The thickening agent may be hydrophobic or hydrophilic andis generally a polymer. Examples of suitable thickening agents for usein the present invention may include synthetic polymers, vinyl polymers,cellulose polymers, natural occurring gelling agents and mixtures of theforegoing. In one embodiment of the present invention, the thickeningagent should exhibit a viscosity of about 1,000 cps to 500,000 cps,preferably 5,000 cps to 250 cps and most preferably about 10,000 cps to100,000 cps when a 2% aqueous solution of the thickening agent isprepared.

Examples of synthetic polymers that may be used as thickening agentsinclude polyacrylic acids or poly(1-carboxyethylene),carboxypolymethylenes prepared from acrylic acid cross-linked with allylethers of (polyalkyl) sucrose or pentaerythritol (e.g. CARBOPOL®940/941/980/981/1342/1382 and carbamer polymers such as carbomer934P/974P), sodium acrylate polymers (e.g. AQUAKEEP™ J-550/J-400), otherpolycarboxylic acids and alkyl acrylate polymers (e.g. PEMULEN®).

Examples of the vinyl polymers that may be used as thickening agentsinclude carboxyvinyl polymers, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl methyl ether, polyvinyl ether and polyvinyl sulfonates.

Examples of cellulose polymers that may be used as thickening agentsinclude hydroxypropyl cellulose, hydroxypropylmethyl cellulose,hydroxypropylethyl cellulose, hydroxypropylbutyl cellulose,hydroxypropylpentyl cellulose, hydroxyethyl cellulose, ethylcellulose,carboxymethyl cellulose and cellulose acetate.

Examples of natural gelling agents that may be used as thickening agentsinclude, dextran, gaur-gum, tragacanth, xanthan gum, sodium alginate,sodium pectinate, acacia gum, Irish moss, karaya gum, guaiac gum, locustbean gum, etc., while natural high molecular weight compounds include,among others, various proteins such as casein, gelatin, collagen,albumin (e.g. human serum albumin), globulin, fibrin, etc. and variouscarbohydrates such as cellulose, dextrin, pectin, starches, agar,mannan, and mixtures of the foregoing.

Additional compounds that may be used as thickening agents arepolyethylene compounds (e.g. polyethylene glycol, etc.), polysaccharides(e.g., polysucrose, polyglucose, polylactose, etc.) and salts thereof,acrylic acid esters, alkoxybutyninpolymers (e.g.,polyoxyethylene-polyoxypropylene copolymers such as the PLURONIC® lineof BASF, Parsippany, N.J.), polyethylene oxide polymers, polyethers,gelatin succinate, colloidal magnesium aluminum silicate (which may beuseful as a gel stabilizer in conjunction with another gelling agent)and petroleum jelly.

The amount of thickening agent employed in a gel for use with thepresent invention may vary depending on the specific result to beachieved. However, in one aspect, the amount of gelling agent may befrom about 0.05% to about 10%, preferably about 0.1% to about 5 wt % andmost preferably about 0.1% to about 3 wt % based upon the total weightof the non-occluded oxybutynin composition.

The amount of thickening agent employed in the non-occluded oxybutynincomposition should impart a viscosity to the non-occluded oxybutynincomposition of about 1,000 cps to about 200,000 cps, preferably about2,500 cps to about 100,000 cps and most preferably about 5,000 cps toabout 75,000 cps.

A non-occluded oxybutynin gel composition useful in the presentinvention may also optionally comprise up to about 10 wt % of alipophilic or hydrophobic agent, which may serve as an emollient oranti-irritant. Emollients and anti-irritants suitable for use in thepresent invention may include lipophilic agents such as, but not limitedto, fatty materials such as fatty alcohols of about 12 to 20 carbonatoms, fatty acid esters having about 12 to 20 carbon atoms in the fattyacid moiety, petrolatum, mineral oils, and plant oils such as soybeanoil, sesame oil, almond oil, aloe vera gel, glycerol, and allantoin.

A non-occluded oxybutynin gel composition useful in the presentinvention may also comprise a pH adjusting agent. The pH adjusting agentmay help reduce irritation and/or aid in obtaining proper gelling.Examples of some pH adjusting agents that may be used include, but arenot limited to, organic amines (e.g., methylamine, ethylamine,di/trialkylamines, alkanolamines, dialkanolamines, triethanolamine),carbonic acid, acetic acid, oxalic acid, citric acid, tartaric acid,succinic acid or phosphoric acid, sodium or potassium salts thereof,hydrochloric acid, sodium hydroxide, ammonium hydroxide, potassiumhydroxide and mixtures thereof. The pH of the non-occluded oxybutyningel composition should be about 4 to about 11, preferably about 4.5 toabout 9 and most preferably about 5 to about 7.

The non-occluded oxybutynin gel composition that may be used in thepresent invention may further comprise conventional processing andaesthetic aids such as chelating agents, surfactants, permeationenhancers, preservatives, anti-microbial agents, antibacterial agents,antioxidants, lubricants and mixtures of any of the foregoing. A moredetailed discussion of these conventional processing and aesthetic aidscan be found in U.S. Pat. No. 7,179,483 which is incorporated herein byreference.

The device for storing and administering a non-occluded oxybutynintopical composition prepared in accordance with the present inventionshould prevent the non-occluded oxybutynin topical composition fromdegrading when stored for at least one year, preferably two years orlonger. For example, the device when filled with the non-occludedoxybutynin composition and sealed can be stored for 26 weeks, 52 weeks,104 weeks or longer without exhibiting any adverse effect on thenon-occluded oxybutynin composition such as a substantially loss ofsolvent, substantial change in pH or degradation of the oxybutynin.After storage the device should also be able to with stand pressure ofat least 20 pounds, preferably at least 30 pounds and most preferably atleast 50 pounds without bursting.

One embodiment of the present invention will allow the non-occludedoxybutynin topical composition to be stored at 25° C. and 60% relativehumidity for twenty-six (26) weeks. After storage for 26 weeks in thesealed device, the non-occluded oxybutynin composition should exhibitthe parameters described in TABLE 1.

TABLE 1 Parameter Preferred More Preferred Most Preferred Oxybutynin90-110% of labeled 90-110% of labeled 90-110% of Content claim claimlabled claim PCGE NMT 0.2% NMT 0.15% NMT 0.1% PCGA NMT 2.0% NMT 1.0% NMT0.5% Individual NMT 0.2% NMT 0.175% NMT 0.15% Unknown Total NMT 1.0% NMT0.75% NMT 0.5% Unknown Solvent NMT 20% change NMT 15% change NMT 10%change pH NMT 1 pH change NMT 0.75 pH NMT 0.5 pH change change NMT isNot More Than PCGE is Phenylcyclohexyl glycolic acid ethyl ester, alsoknown as ethylphenyl-cyclohexyl glycolate, cyclohexylphenyl-glycolicacid, and cyclohexyl-mandelic acid ethyl ester. PCGA is USP OxybutyninRelated Compound A, also known as Phenylcyclohexylglycolic acid,cyclohexylmandelic acid, oxybutacide, CHMA.

With respect to the change in solvent, the above TABLE 1 indicates thechange in solvent after storage should not vary by more than 20%, 15% or10% of the initial amount of solvent. This means, if the initial amountof solvent was 100 mg of ethanol, after storage under the appropriatetime and conditions, the amount of solvent should not be less than 80mg, 85 mg or 90 mg respectively. Similarly, with respect to the changein pH, if the initial pH of the non-occluded oxybutynin topicalcomposition is 6, after storage, the pH should be no lower than 5 and nohigher than 7 for the NMT 1 pH criteria and should not be lower than 5.5or higher than 6.5 for the NMT 0.5 pH criteria.

Another embodiment of the present invention will allow the non-occludedoxybutynin topical composition to be stored at 25° C. and 60% relativehumidity for fifty-two (52) weeks. After storage for 52 weeks in thesealed device, the non-occluded oxybutynin composition should exhibitthe parameters described in TABLE 2.

TABLE 2 Parameter Preferred More Preferred Most Preferred Oxybutynin90-110% of labeled 90-110% of labeled 90-110% of Content claim claimlabled claim PCGE NMT 0.2% NMT 0.17% NMT 0.15% PCGA NMT 2.0% NMT 1.7%NMT 1.0% Individual NMT 0.2% NMT 0.18% NMT 0.16% Unknown Total NMT 1.0%NMT 0.80% NMT 0.65% Unknown Solvent NMT 20% change NMT 15% change NMT10% change pH NMT 1 pH change NMT 0.75 pH NMT 0.5 pH change change

A further embodiment of the present invention will allow thenon-occluded oxybutynin topical composition to be stored at 25° C. and60% relative humidity for one hundred four (104) weeks. After storagefor 104 weeks in the sealed device, the non-occluded oxybutynincomposition should exhibit the parameters described in TABLE 2.

A still further embodiment of the present invention will allow thenon-occluded oxybutynin topical composition to be stored at 40° C. and75% relative humidity for thirteen (13) weeks. After storage for 13weeks in the sealed device, the non-occluded oxybutynin compositionshould exhibit the parameters described in TABLE 3.

TABLE 3 Parameter Preferred More Preferred Most Preferred Oxybutynin90-110% of labeled 90-110% of labeled 90-110% Content claim claim oflabled claim PCGE NMT 0.2% NMT 0.15% NMT 0.1% PCGA NMT 2.0% NMT 1.0% NMT0.5% Individual NMT 0.2% NMT 0.175% NMT 0.15% Unknown Total NMT 1.0% NMT0.75% NMT 0.5% Unknown Solvent NMT 20% change NMT 15% change NMT 10%change pH NMT 1 pH change NMT 0.75 pH NMT 0.5 pH change change

An additional embodiment of the present invention will allow thenon-occluded oxybutynin topical composition to be stored at 40° C. and75% relative humidity for twenty-six (26 weeks). After storage for 26weeks in the sealed device, the non-occluded oxybutynin compositionshould exhibit the parameters described in TABLE 4.

TABLE 4 Parameter Preferred More Preferred Most Preferred Oxybutynin90-110% of labeled 90-110% of labeled 90-110% of Content claim claimlabeled claim PCGE NMT 0.2% NMT 0.17% NMT 0.15% PCGA NMT 2.0% NMT 1.7%NMT 1.0% Individual NMT 0.2% NMT 0.18% NMT 0.16% Unknown Total NMT 1.0%NMT 0.80% NMT 0.65% Unknown Solvent NMT 20% change NMT 15% change NMT10% change pH NMT 1 pH change NMT 0.75 pH NMT 0.5 pH change change

Due to the high solvent content of the non-occluded oxybutynincompositions used in the present invention there is a chance thatmaterial from the laminate forming the device may leach from thelaminate into the non-occluded oxybutynin composition. This leachingeffect is undesirable and should be kept to a minimum or eliminatedcompletely. In order to avoid the unwanted leaching of laminatecompounds into the non-occluded oxybutyinin composition, the laminateshould be selected so upon storage of the filled and sealed device, thetotal amount of leachable materials is not more than 1% of the totalweight of the non-occluded oxybutynin composition. More importantly,after storage of the filled and sealed device, no individual leachablematerial should exceed the acceptable daily intake limits established bythe United States Food and Drug Administration.

One embodiment of the present invention, such as an LLDPE device, willallow the total leachable concentration in the non-occluded oxybutynincomposition after storage in a filled and sealed device for 52 weeks at25° C. and 60% relative humidity to be not more than 300 ppm, preferablynot more than 200 ppm and most preferably not more than 150 ppm.

Another embodiment of the present invention, such as an LLDPE device,will allow the total leachable concentration in the non-occludedoxybutynin composition after storage in a filled and sealed device for104 weeks at 25° C. and 60% relative humidity to be not more than 300ppm, preferably not more than 200 ppm and most preferably not more than150 ppm.

A further embodiment of the present invention, such as a BAREX® device,will allow the total leachable concentration in the non-occludedoxybutynin composition after storage in a filled and sealed device for52 weeks at 25° C. and 60% relative humidity to be not more than 100ppm, preferably not more than 50 ppm and most preferably not more than25 ppm.

A still further embodiment of the present invention, such as a BAREX®device, will allow the total leachable concentration in the non-occludedoxybutynin composition after storage in a filled and sealed device for104 weeks at 25° C. and 60% relative humidity to be not more than 100ppm, preferably not more than 50 ppm and most preferably not more than25 ppm.

The “leachable” materials are determined by first conducting anextraction study on samples of the laminate and samples of the firstpolymer layer of the laminate (14) to identify potential leachablecomponents. Once the potential leachable components are identified, thestorage and administration device is filled with an appropriate dose ofthe non-occluded oxybutynin composition and sealed. The filled andsealed device is stored at 25° C. and 60% relative humidity for therequired time period. After storage, the device is opened and thenon-occluded oxybutynin composition is analyzed using an appropriateanalytical technique such as high performance liquid chromatography(HPLC).

The initial extraction study to determine the potential leachablecomponents may be conducted by placing a sample of the laminate and/orsample of the first polymer layer in a Soxhlet extraction apparatus oran open bottle along with a suitable solvent such as alcohol, water oralcohol and water mixtures. The solvent is then analyzed by gaschromatography/mass spectroscopy (GCMS); high performance liquidchromatography (HPLC) or liquid chromatography/mass spectroscopy (LCMS)to determine the identity of any potential leachable compound.

The present invention also relates to a method for treating humanpatients suffering from overactive bladder comprising the steps of: a)providing a storage and administration device comprising a single ordaily dose of a non-occluded oxybutynin composition to a human; b)dispensing the single or daily dose of the oxybutynin composition fromthe storage and administration device; and c) applying the single ordaily dose of the oxybutynin composition to the skin of the humanpatient, such as the abdomen, thighs, arms or combination of theforegoing.

The storage and administration device employed in the above describedmethod may be a pouch or sachet as described previously and is preparedfrom a laminate material comprising, from inside out, a first polymerlayer (14), an adhesive (12) and a metal foil layer (10) wherein theadhesive layer (12) adheres the first polymer layer (14) to the metalfoil layer (10).

The non-occluded oxybutynin composition is dispensed from the storageand administration device by opening or unsealing at least a portion ofone of the device's sealed edges and applying pressure to an end of thedevice that is opposite of the opened or unsealed portion to force thecontents of the reservoir from the device. Once the non-occludedoxybutynin composition is dispensed from the reservoir of the device,the device should be disposed.

The non-occluded oxybutynin composition 5 employed in the abovedescribed method may be a gel, cream or lotion as previously described.One embodiment of the method of the present invention employs anoxybutynin gel that comprises oxybutynin or a pharmaceuticallyacceptable salt thereof, a solvent and a thickening agent as describedpreviously. The amount of non-occluded oxybutynin composition in thedevice for the single or daily dose should comprise about 0.25 grams toabout 5 grams of which about 3% to about 15% based upon total weight ofthe composition is oxybutynin.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following are provided by way of example only and are by no meansintended to be limiting.

EXAMPLE 1 Oxybutynin 10% Gel

A non-occluded oxybutynin chloride gel was prepared with the followingcomposition:

Component % by Weight Grams per dose Oxybutynin chloride 10.0 0.100Purified Water, USP 10.5 0.105 Alcohol, USP 73.3 0.733 Glycerin, USP 1.00.010 Sodium Hydroxide 3.2 0.032 Solution, 2N Hydroxypropyl 2.0 0.020Cellulose, NF (KLUCEL ® HF) Total 100 1.0

The above composition was prepared by mixing the alcohol, oxybutyninchloride and glycerin in a jacketed mixer for about 5 minutes. TheKLUCEL® HF was slowly added while continuing to mix. The water andsodium hydroxide solution are added to obtain a pH of about 6. After allingredients were added, the mixing continued for 1.5 to 3 hours. Thetemperature of the mixer was maintained between 15-35° C.

EXAMPLE 2 Oxybutynin 4.4% Gel

A non-occluded oxybutynin chloride gel was prepared according to theprocedure described in Example 1 to produce the following composition:

Component % by Weight Grams per dose Oxybutynin chloride 4.40 0.132Purified Water, USP 18.0 0.540 Alcohol, USP 73.3 2.199 Glycerin, USP 1.00.030 Sodium Hydroxide 1.3 0.039 Solution, 2N Hydroxypropyl 2.0 0.060Cellulose, NF (KLUCEL ® HF) Total 100 3.0

EXAMPLE 3 Oxybutynin 13.2% Gel

A non-occluded oxybutynin hydrochloride gel was prepared according tothe procedure described in Example 1 to produce the followingcomposition:

Component % by Weight Grams per dose Oxybutynin chloride 13.2 0.132Purified Water, USP 5.90 0.059 Alcohol, USP 73.3 0.733 Glycerin, USP 1.00.010 Sodium Hydroxide 4.6 0.046 Solution, 2N Hydroxypropyl 2.0 0.020Cellulose, NF (KLUCEL ® HF) Total 100 1.0

EXAMPLE 4

A device in accordance with the present invention was prepared using aBAREX® laminate that had the following composition from inside(oxybutynin contact) the device to outside: 1.5 mil BAREX®/adhesive/0.35mil aluminum foil/81b LDPE/white 261b C1S paper. The BAREX® resin is anacrylonitrile-methyl acrylate copolymer. The BAREX® laminate wascommercially available from Graphic Packaging International, Inc. ofShaumburg, Ill., USA under the designation LC FLEX No. 81920 (formerlyS-6037).

A Klockner LA-160 Packager machine was set up using a single roll of theBAREX® laminate. The laminate was 12 inches wide and slit into twohalves. The two halves were guided together such that the BAREX® resinsides of the two halves opposed each other. The two 6 inch webs werethen heat sealed together to form three lanes of 3-sided sachets.

The oxybutynin chloride gel of Example 1 was delivered into each sachetusing individually-adjustable, precision metering pumps (one for eachlane). The pumps were primed by applying nitrogen pressure to thepressure/storage vessel. After priming, each pump deliveredapproximately 1 gram of the oxybutynin chloride gel of Example 1 to eachreservoir of the 3-sided sachets. The final side of each sachet was thenheat sealed. The three sachets were then split apart and cut intoindividual sachets.

The cycle or web speed and sealing temperatures will depend upon themachines and equipment employed. In this Example, a longitudinal heatseal temperature of about 150° C. (145-155° C.), a cross heat sealtemperature of about 150° (145-155° C.) and a cycle speed of 30-50cycles per minute were employed.

The 1 g sachets prepared in this Example were tested using a motorizedtest stand which slowly squeezed the sachets between two platens. The 1g sachets received 30 and 50 pounds of pressure without bursting.

The sachets prepared in this Example were also subjected to stabilitytesting at 25° C. and 60% relatively humidity for at least 26 and 52weeks and 40° C. and 75% relatively humidity for at least 13 and 26weeks. The samples exhibited a stability that met the preferred, morepreferred and most preferred values contained in TABLES 1-4 above.

EXAMPLE 5

A device in accordance with the present invention was prepared using aBAREX® laminate that had the following composition from inside(oxybutynin contact) the device to outside: 1.5 mil BAREX®/adhesive/0.35mil aluminum foil/81b LDPE/white 261b C1S paper. The BAREX® resin is anacrylonitrile-methyl acrylate copolymer. The BAREX® laminate wascommercially available from Graphic Packaging International, Inc. ofShaumburg, Ill., USA under the designation LC FLEX No. 81920 (formerlyS-6037).

1 gram sachets using the oxybutynin chloride composition of Example 1were prepared according to the procedure described in Example 4 with alongitudinal heat seal temperature of 165-180° C., a cross heat sealtemperature of 165-180° C. and a cycle speed of 50-60 cycles per minutewere employed.

The 1 g sachets prepared in this Example were tested using a motorizedtest stand which slowly squeezed the sachets between two platens. The 1g sachets received 30 pounds of pressure without bursting.

EXAMPLE 6

A device in accordance with the present invention was prepared using anLLDPE laminate that had the following composition from inside(oxybutynin contact) the device to outside: LLDPE/EAA (ethylene/acrylicacid copolymer) resin/0.35 mil aluminum foil/white primacor resinblend/water-base extrusion primer/proprietary treat process/polyester.The LLDPE laminate was commercially available from Alcoa FlexiblePackaging of Richmond, Va. under the name PHARMA POUCH PP 1312.

1 gram sachets using the oxybutynin chloride composition of Example 1were prepared according to the procedure described in Example 4 with alongitudinal heat seal temperature of about 130° C. (125-135° C.), across heat seal temperature of about 130° C. (125-135° C.) and a cyclespeed of about 23 (20-26) cycles per minute.

The 1 g sachets prepared in this Example were tested using a motorizedtest stand which slowly squeezed the sachets between two platens. The 1g sachets received 50 pounds of pressure without bursting.

The sachets prepared in this Example were also subject to stabilitytesting at 25° C. and 60% relatively humidity for at least 26 and 52weeks and 40° C. and 75% relatively humidity for at least 13 and 26weeks. The samples exhibited a stability that met the preferred, morepreferred and most preferred values contained in TABLES 1-4 above.

EXAMPLE 7

A device in accordance with the present invention was prepared using anLLDPE laminate that had the following composition from inside(oxybutynin contact) the device to outside: LLDPE/EAA (ethylene/acrylicacid copolymer) resin/0.35 mil aluminum foil/white primacor resinblend/water-base extrusion primer/proprietary treat process/polyester.The LLDPE laminate was commercially available from Alcoa FlexiblePackaging of Richmond, Va. under the name PHARMA POUCH PP 1312.

3 gram sachets using the oxybutynin chloride composition of Example 2were prepared according to the procedure described in Example 5 except alongitudinal heat seal temperature of about 185° C. (180-190° C.), across heat seal temperature of about 185° C. (180-190° C.) and a cyclespeed of about 50 (45-55) cycles per minute were employed.

The 3 g sachets prepared in this Example were tested using a motorizedtest stand which slowly squeezed the sachets between two platens. The 3g sachets received 100 pounds of pressure without bursting.

EXAMPLE 8

A device in accordance with the present invention was prepared using anLLDPE laminate that had the following composition from inside(oxybutynin contact) the device to outside: LLDPE/EAA (ethylene/acrylicacid copolymer) resin/0.35 mil aluminum foil/white primacor resinblend/water-base extrusion primer/proprietary treat process/polyester.The LLDPE laminate was commercially available from Alcoa FlexiblePackaging of Richmond, Va. under the name PHARMA POUCH 1312.

1 gram sachets using the oxybutynin chloride composition of Example 3were prepared according to the procedure described in Example 5 except alongitudinal heat seal temperature of about 155° C. (150-160° C.), across heat seal temperature of about 190° C. (185-195° C.) and a cyclespeed of about 23 (20-26) cycles per minute were employed.

The 1 g sachets prepared in this Example were tested using a motorizedtest stand which slowly squeezed the sachets between two platens. The 1g sachets received 50 pounds of pressure without bursting.

COMPARATIVE EXAMPLE 1

A device not in accordance with the present invention was prepared usinga 2 mil LDPE laminate obtained from Tekni-Plex Inc. of Flemington, N.J.The laminate had the following composition from inside (oxybutynincontact) the device to outside: 2 mil LDPE/10.0# ethylene-acrylic acidcopolymer/0.00035 mil aluminum foil/10.0#LDPE/26# C1S Paper. All theattempts to create an oxybutynin chloride topical gel sachet resulted inleaking pouches.

EXAMPLE 9

A leachable study was conducted on a product as described in Example 4.In the first part of the study samples of the BAREX® laminate andsamples of acrylonitrile-methyl acrylate copolymer were exposed toaggressive Soxhlet and open bottle extractions using four differentsolvent systems: 1) 190 proof ethanol (HPLC grade); 2) 85% of 190 proofethanol (HPLC grade) and 15% nanopure deionized water; 3) isopropanol(HPLC grade) and 4) nanopure deionized water. The extracts of the fulllaminate and acrylonitrile-methylacrylate copolymer were analyzed byGCMS, HPLC and LC/MS. Based upon the extraction testing the followingcompounds were identified as potential leachable components:

-   -   Lauryl alcohol;    -   Lauryl acrylate;    -   Nonylphenol;    -   Di-octyl maleate;    -   Di-octyl fumarate;    -   Butyl stearate; and    -   Tris-nonylphenyl phosphate

The extraction study also identified nonylphenyl phosphate as apotential leachable, however, it was later determined that is compoundwas generated as an artifact of the hydrolytic oxidation of thetris-nonylphenyl phosphate during the analysis.

1 gram sachets prepared according to the procedure described in Example4 were stored at 25° C. and 60% relatively humidity for 122 weeks. Afterstorage, the contents of a sachet were transferred to a glassscintillation vial and approximately 2 g of acetonitrile was added tothe mixture vortex. Samples were prepared in triplicate and analyzed byGCMS. The GCMS test results indicated the stored gel contained:

-   less than 1 ppm of lauryl alcohol;-   less than 1 ppm of lauryl acrylate;-   less than 1 ppm of nonylphenol;-   less than 1 ppm of di-octyl maleate;-   less than 1 ppm of di-octyl fumarate; and-   less than 1 ppm of butyl stearate.

Due to the thermal instability of tris-nonylphenyl phosphate, thevortexed sample was also analyzed by HPLC and found to contain less than1 ppm of tris-nonylphenyl phosphate.

1 gram sachets prepared according to the procedure described in Example4 were stored at 25° C. and 60% relatively humidity for 63 and 65 weeks.After storage, the contents of a sachet were transferred to a glassscintillation vial and approximately 2 g of acetonitrile was added tothe mixture vortex. Samples were again prepared in triplicate andanalyzed by GCMS. The GCMS test results indicated the stored gelcontained:

-   less than 1 ppm of lauryl alcohol;-   less than 1 ppm of lauryl acrylate;-   less than 1 ppm of di-octyl maleate;-   less than 1 ppm of di-octyl fumarate; and-   less than 1 ppm of butyl stearate.

The GCMS analysis also indicated the gel stored for 63 and 65 weekscontained between less than 1 ppm and 6.46 ppm of nonylphenol.Specifically, the tests on the 63 week sample yielded values of 1.12ppm, 1.32 ppm and less than 1 ppm for the nonylphenol, and the tests onthe 65 week sample yielded values of 6.46 ppm, 4.23 ppm and 4.68 ppm.

The vortexed sample was also analyzed by HPLC and found to contain lessthan 1 ppm of tris-nonylphenyl phosphate.

EXAMPLE 10

A leachable study was conducted on a product as described in Example 6.In the first part of the study samples of the PHARMA POUCH PP1312laminate and samples of the LLDPE polymer were exposed to aggressiveSoxhlet and open bottle extractions using four different solventsystems: 1) 190 proof ethanol (HPLC grade); 2) 85% of 190 proof ethanol(HPLC grade) and 15% nanopure deionized water; 3) isopropanol (HPLCgrade) and 4) nanopure deionized water. The extracts of the fulllaminate and LLDPE polymer were analyzed by GCMS, HPLC and LC/MS. Basedupon the extraction testing the following compounds were identified aspotential leachable components:

-   Erucamide (Z-docos-13-enamide)(CAS #112-84-5);-   tris-2,4-di-tert-butylphenyl phosphate (CAS #6683-19-8) (IGRAFOS 168    phosphate which is an oxidation product of Igrafos 168 known to be    used by Alcoa as an antioxidant);-   tris-2,4-di-tert-butylphenyl phosphite (CAS #31570-04-4) (IGRAFOS    168); and-   Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (CAS    #2082-79-3) (IRGANOX 1076 also known to be used by Alcoa as an    antioxidant).

1 gram sachets prepared according to the procedure described in Example6 were stored at 25° C. and 60% relatively humidity for 121 weeks, 104weeks and 99 weeks. After storage, the contents of a sachet weretransferred to a glass scintillation vial and approximately 2 g ofacetonitrile was added to the mixture vortex. Samples were prepared intriplicate and analyzed by HPLC and LCMS and found to contain thefollowing leachables:

IRGAFOS 168 Sample Erucamide Phosphate IRGANOX 1076 121 weeks 26.0 ppm102.1 ppm 10.82 ppm  121 weeks 23.1 ppm  60.0 ppm 8.06 ppm 121 weeks21.1 ppm 104.3 ppm 9.59 ppm 104 weeks 23.2 ppm 109.1 ppm 8.61 ppm 104weeks 17.1 ppm 102.3 ppm 9.55 ppm 104 weeks 29.1 ppm 121.5 ppm 11.50ppm   99 weeks 16.3 ppm 100.1 ppm 12.81 ppm   99 weeks 21.3 ppm  85.7ppm 9.37 ppm  99 weeks 23.6 ppm  95.8 ppm 8.96 ppm average 22.3 ppm 97.9 ppm  9.9 ppm

Although IRGAFOS 168 was reported in the extraction study as a potentialleachable only its oxidation product IRGAFOS 168 phosphate was measureddue to the poor stability of IRGAFOS 168 in solution and its rapidconversion to IRGAFOS 168 phosphate.

While certain preferred and alternative embodiments of the presentinvention have been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

The term “comprising” as used in the following claims is an open-endedtransitional term that is intended to include additional elements notspecifically recited in the claim. The term “consisting essentially of”as used in the following claims is a partially closed transitionalphrase and is intended to include the recited elements plus anyunspecified elements that do not materially affect the basic and novelcharacteristics of the claim. For example, an outermost layer on thedisclosed laminates that are embossed or printed with indicia would beincluded in the meaning of “consisting essentially of”, even if notspecifically recited. The term “consists of” as used in the followingclaims is intended to indicate that the claim is restricted to therecited elements.

The invention claimed is:
 1. A device for storing and administering anon-occluded oxybutynin topical composition comprising: a) anon-occluded oxybutynin topical composition comprising: i) atherapeutically effective amount of oxybutynin; ii) a thickening agentand iii) 50% or more based upon the weight of the non-occludedoxybutynin topical composition of a solvent; b) a reservoir for thenon-occluded oxybutynin topical composition; and c) a laminatesurrounding the reservoir and non-occluded oxybutynin topicalcomposition comprising: i) a first polymer that is in contact with thenon-occluded oxybutynin topical composition; and ii) a metal foil boundto the first polymer layer; and d) a notch or partial scoring of thelaminate surrounding the reservoir and non-occluded oxybutynin topicalcomposition wherein the notch or partial scoring facilitates the openingof the device for dispensing the non-occluded oxybutynin topicalcomposition from the device; and wherein the device can withstand 30pounds of pressure without bursting when squeezed between two platens ofa motorized test stand and when the device is stored at 25° C. and 60%relative humidity for twenty-six weeks the non-occluded oxybutynintopical composition contains not more than 0.2% of phenylcyclohexylglycolic acid ethyl ester (PCGE); not more than 2.0%phenylcyclohexylglycolic acid (PCGA) and there is not more than a 20%change in the solvent content.
 2. The device of claim 1 wherein thelaminate further comprises an adhesive layer between the first polymerlayer and the metal foil for bonding the metal foil to the first polymerlayer.
 3. The device of claim 1 wherein the laminate further comprisesan additional layer for embossing or printing descriptive information.4. The device of claim 1 wherein the non-occluded oxybutynin topicalcomposition is a gel, cream or lotion.
 5. The device of claim 4 whereinthe non-occluded oxybutynin topical composition is a gel.
 6. The deviceof claim 1 wherein the non-occluded oxybutynin topical compositioncomprises about 2% to about 20% based upon the total weight of thecomposition of oxybutynin.
 7. The device as defined in claim 1 whereinthe oxybutynin is oxybutynin chloride.
 8. The device of claim 1 whereinthe solvent comprises at least 60% of the total weight of thecomposition.
 9. The device of claim 1 that can withstand 50 pounds ofpressure without bursting.
 10. The device of claim 1 that can withstand100 pounds of pressure without bursting.
 11. The device of claim 1wherein after storage at 25° C. and 60% relative humidity for fifty-twoweeks, the non-occluded oxybutynin topical composition contains not morethan 0.17% of PCGE; not more than 1.7% of PCGA and there is not morethan a 15% change in the solvent content.
 12. The device of claim 11wherein after storage at 25° C. and 60% relative humidity for fifty-twoweeks, the non-occluded oxybutynin topical composition contains not morethan 0.15% of PCGE; not more than 1.0% of PCGA and there is not morethan a 10% change in the solvent content.
 13. The device of claim 1wherein after storage at 40° C. and 75% relative humidity for thirteenweeks, the non-occluded oxybutynin topical composition contains not morethan 0.15% of PCGE; not more than 1.0% of PCGA and there is not morethan a 15% change in the solvent content.
 14. The device of claim 13wherein after storage at 40° C. and 75% relative humidity for thirteenweeks, the non-occluded oxybutynin topical composition contains not morethan 0.10% of PCGE; not more than 0.50% of PCGA and there is not morethan a 10% change in the solvent content.
 15. The device of claim 1wherein after storage at 40° C. and 75% relative humidity for twenty-sixweeks, the non-occluded oxybutynin topical composition contains not morethan 0.17% of PCGE; not more than 1.7% of PCGA and there is not morethan a 15% change in the solvent content.
 16. The device of claim 15wherein after storage at 40° C. and 75% relative humidity for twenty-sixweeks, the non-occluded oxybutynin topical composition contains not morethan 0.15% of PCGE; not more than 1.0% of PCGA and there is not morethan a 10% change in the solvent content.
 17. The device of claim 1wherein the reservoir is formed by sealing at least one edge of thelaminate.
 18. The device of claim 17 wherein the reservoir is formed bysealing more than one edge of the laminate.
 19. The device of claim 17wherein the seal is a destructive seal.
 20. A device for storing andadministering a non-occluded oxybutynin topical composition comprising:a) a non-occluded oxybutynin topical composition with a pH of about 4.5to about 9 comprising: i) about 2% to about 20% based upon the weight ofthe non-occluded oxybutynin topical composition of oxybutynin; ii) about0.05% to about 10% based upon the weight of the non-occluded oxybutynintopical composition of a thickening agent; and iii) 50% or more basedupon the weight of the non-occluded oxybutynin topical composition of asolvent; b) a reservoir for the non-occluded oxybutynin topicalcomposition; and c) a laminate surrounding the reservoir andnon-occluded oxybutynin topical composition comprising: i) a firstpolymer that is in contact with the non-occluded oxybutynin topicalcomposition; and ii) a metal foil bound to the first polymer layerwherein the reservoir is created by forming at least one destructiveseal on the laminate; and d) a notch or partial scoring of the laminatesurrounding the reservoir and non-occluded oxybutynin topicalcomposition wherein the notch or partial scoring facilitates the openingof the device for dispensing the non-occluded oxybutynin topicalcomposition from the device and wherein the device can withstand 50pounds of pressure without bursting when squeezed between two platens ofa motorized test stand; wherein when the device is stored at 25° C. and60% relative humidity for twenty-six weeks, the non-occluded oxybutynintopical composition contains not more than 0.15% of phenylcyclohexylglycolic acid ethyl ester (PCGE), not more than 1.00% ofphenylcyclohexylglycolic acid (PCGA), there is not more than a 15%change in the solvent content and not more than a 0.75 change in pH; andwherein when the device is stored for thirteen weeks at 40° C. and 75%relative humidity, the non-occluded oxybutynin topical compositioncontains not more than 0.15% of PCGE, not more than 1.00% of PCGA, thereis not more than a 15% change in the solvent content and not more than a0.75 change in pH.
 21. A method for treating human patients sufferingfrom overactive bladder comprising the steps of a) providing a storageand administration device as defined in claim 1 to a human; b)dispensing a single or daily dose of the oxybutynin composition from thedevice; and c) applying the single or daily dose of the oxybutynincomposition to a skin surface of the human patient.
 22. A method fortreating human patients suffering from overactive bladder comprising thesteps of a) providing a storage and administration device as defined inclaim 20 to a human; b) dispensing a single or daily dose of theoxybutynin composition from the device; and c) applying the single ordaily dose of the oxybutynin composition to a skin surface of the humanpatient.
 23. The device of claim 1 wherein the non-occluded oxybutynintopical composition does not include a backing member.
 24. The device ofclaim 20 wherein the non-occluded oxybutynin topical composition doesnot include a backing member.